“Quantified Health and Disease”

Lecture for the Osher Lifetime Learning Institute
UCSD Extension
Calit2’s Qualcomm Instit...
Chronic Disease Has a
Huge National Economic Impact
The CDC States:
“Chronic Diseases Are the Most Preventable”
www.cdc.gov/chronicdisease/resources/publications/aag/chronic....
During the Last 15 Years, the Fraction of the Population
That is Obese Has Greatly Increased
Source: Behavioral Risk Facto...
Over 1/3 of American Adults are Obese:
This is a Major Driver of Increased Chronic Disease

Obesity-related conditions inc...
I Arrived in La Jolla in 2000of My Body andin the Midwest
By Measuring the State After 20 Years “Tuning” It
Using Nutritio...
I Used a Variety of Emerging Personal Sensors
To Quantify My Body & Drive Behavioral Change
Withings/iPhoneBlood Pressure
...
Consumer Self Measurement is Exploding
Totally Outside of the Medical Complex
From the First San Francisco QS Meetup in 20...
In 2013 QS Went Mainstream
The Self-Monitoring Business
Has Reached Market Takeoff
• MyFitnessPal
– 40 Million Users
– Aug 2013 Raised $18M Series A,...
RevUp! Completes the Behavior Feedback Loop

Source: Samir Damani, MD Revolution
From Measuring Macro-Variables
to Measuring My Internal Variables – What Did I Learn?

www.technologyreview.com/biomedicin...
From One to a Billion Data Points Defining Me:
The Exponential Rise in Body Data in Just One Decade!
Billion:Microbial Gen...
Visualizing Time Series of
150 LS Blood and Stool Variables, Each Over 5-10 Years
Calit2 64 megapixel VROOM
I Discovered I Had Chronic Inflammation by
Tracking Complex Reactive Protein In My Blood Samples
27x Upper Limit

Antibiot...
But by Using Stool Analysis Time Series, I Discovered
I Had Episodically Excursions of My Immune System
Typical
Lactoferri...
Indeed, My Cultured Gut Bacterial Abundance Time Series
Revealed an Oscillatory Microbiome Ecology

LS Data from Yourfutur...
Startups are Already in
the Internal Quantified Self Space!

WellnessFX Just Acquired
By Health Elements
Confirming the IBD Hypothesis:
Finding the “Smoking Gun” with MRI Imaging
Liver

Transverse Colon

Small Intestine

I Obta...
Why Did I Have an Autoimmune Disease like IBD?

Despite decades of research,
the etiology of Crohn's disease
remains unkno...
The Cost of Sequencing a Human Genome
Has Fallen Over 10,000x in the Last Ten Years!

This Has Enabled Sequencing of
Both ...
Single Nucleotide Polymorphisms (SNPs) Make Up
About 90% of All Human Genetic Variation

Person A
SNPs Occur Every
100 to ...
I Wondered if Crohn’s is an Autoimmune Disease,
Did I Have a Personal Genomic Polymorphism?
From www.23andme.com

ATG16L1
...
Fine Time-Resolution Revealed Immune Dysfunction in
the Innate and Adaptive Immune System
LS Data from Yourfuturehealth.co...
I Had Carried Out Observations in Optical, Radio, and X-Ray
on the Andromeda Galaxy in the 1980s
A Galaxy Contains
One Hun...
Now I am Observing the 100 Trillion
Non-Human Cells in My Body
Your Body Has 10 Times
As Many Microbe Cells As Human Cells...
2012 Was
the Year of Human Microbiome
I Spent Decades Studying
the Ecological Dynamics of Coral Reefs

Pristine

Degraded
My 120 Gallon Home Salt Water
Coral Re...
When We Think About Ecological Diversity
We Typically Think of the Wide Range of Animals

But All These Animals Are in One...
Think of These Phyla of Animals When
You Consider the Biodiversity of Microbes Inside You

Phylum
Chordata

Phylum
Cnidari...
However, The Evolutionary Distance Between Your Gut Microbes
Is Much Greater Than Between All Animals

Last Slide

Green C...
Quantifying Our Human Superorganism:
Distribution of Microorganism Ecology on Our Bodies

Nature Reviews
Microbiology
v.9,...
Intense Scientific Research is Underway
on Understanding the Human Microbiome

June 8, 2012

June 14, 2012

From Culturing...
The Adult Healthy Gut Microbiome
Is Remarkably Stable Over Time

Source: Eric Alm, MIT
To Map Out the Dynamics of My Microbiome Ecology
I Partnered with the J. Craig Venter Institute
• JCVI Did Metagenomic
Seq...
We Downloaded Additional Human Gut Microbiome Data
from the NIH For Comparative Analysis
35 “Healthy” Individuals:
1 Point...
We Used SDSC’s Gordon Data-Intensive Supercomputer
to Analyze a Wide Range of Gut Microbiomes
Source: Weizhong Li, Sitao W...
Using Scalable Visualization Allows Comparison of
the Relative Abundance of 200 Microbe Species

Comparing 3 LS Time Snaps...
Lessons from Ecological Dynamics I:
Gut Microbiome Has Multiple Relatively Stable Equilibria

“The Application of Ecologic...
Disease State Has a Different Microbiome Equilibrium
Than Healthy
Expansion of
Actinobacteria

Collapse of
Bacteroidetes

...
Time Series Reveals Ecological Dynamics
of My Gut Microbiome by Phyla
Therapy

Six Metagenomic Time Samples Over 16 Months
Lessons From Ecological Dynamics II:
Invasive Species Dominate After Major Species Destroyed

 ”In many areas following th...
Almost All Abundant Species (≥1%) in Healthy Subjects
Are Severely Depleted in Larry’s Gut Microbiome
Top 20 Most Abundant Microbial Species
In LS vs. Average Healthy Subject
152x
765x
148x

Number Above
LS Blue Bar is Multi...
Next Step: Time Series of Metagenomic Gut Microbiomes
and Immune Variables in an N=100 Clinic Trial

Goal: Understand
The ...
From War to Gardening:
New Therapeutical Tools for Managing the Microbiome

“I would like to lose the language of warfare,...
Where I Believe We are Headed: Predictive,
Personalized, Preventive, & Participatory Medicine
I am Lee Hood’s Lab Rat!

ww...
Thanks to Our Great Team!
UCSD Metagenomics Team

JCVI Team

Weizhong Li
Sitao Wu

Karen Nelson
Shibu Yooseph
Manolito Tor...
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Quantified Health and Disease

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2014.02.06
Calit2 Director Larry Smarr lecture to the Osher Lifelong Learning Institute as part of the Winter 2014 Qualcomm Institute lecture series for Osher.

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Quantified Health and Disease

  1. 1. “Quantified Health and Disease” Lecture for the Osher Lifetime Learning Institute UCSD Extension Calit2’s Qualcomm Institute, UCSD La Jolla, CA February 6, 2014 Dr. Larry Smarr Director, California Institute for Telecommunications and Information Technology Harry E. Gruber Professor, Dept. of Computer Science and Engineering Jacobs School of Engineering, UCSD http://lsmarr.calit2.net
  2. 2. Chronic Disease Has a Huge National Economic Impact
  3. 3. The CDC States: “Chronic Diseases Are the Most Preventable” www.cdc.gov/chronicdisease/resources/publications/aag/chronic.htm “Four common, health-damaging, but modifiable behaviors—tobacco use, insufficient physical activity, poor eating habits, and excessive alcohol use—are responsible for much of the illness, disability, and premature death related to chronic diseases.” -CDC Chronic Disease Prevention and Health Promotion “There is a staggering cost for failing to contain the containable.” An Unhealthy America: The Economic Burden of Chronic Disease Milken Institute Report 2007
  4. 4. During the Last 15 Years, the Fraction of the Population That is Obese Has Greatly Increased Source: Behavioral Risk Factor Surveillance System, CDC No State >20% (Obese is BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No State <20%
  5. 5. Over 1/3 of American Adults are Obese: This is a Major Driver of Increased Chronic Disease Obesity-related conditions include heart disease, stroke, type 2 diabetes, and certain types of cancer, some of the leading causes of preventable death. --CDC www.cdc.gov/obesity/data/adult.html
  6. 6. I Arrived in La Jolla in 2000of My Body andin the Midwest By Measuring the State After 20 Years “Tuning” It Using Nutrition and Exercise, Ithe Obesity Trend and Decided to Move Against Became Healthier Age 41 Age 51 Age 61 1999 2000 1999 1989 I Reversed My Body’s Decline By Quantifying and Altering Nutrition and Exercise http://lsmarr.calit2.net/repository/LS_reading_recommendations_FiRe_2011.pdf 2010
  7. 7. I Used a Variety of Emerging Personal Sensors To Quantify My Body & Drive Behavioral Change Withings/iPhoneBlood Pressure FitBit Daily Steps & Calories Burned MyFitnessPalCalories Ingested Azumio-Heart Rate Withings WiFi Scale Daily Weight Zeo-Sleep
  8. 8. Consumer Self Measurement is Exploding Totally Outside of the Medical Complex From the First San Francisco QS Meetup in 2008 To 116 Cities in 37 Countries in Four Years
  9. 9. In 2013 QS Went Mainstream
  10. 10. The Self-Monitoring Business Has Reached Market Takeoff • MyFitnessPal – 40 Million Users – Aug 2013 Raised $18M Series A, Led by Kleiner Perkins • Fitbit – Has Raised ~$70M • BodyMedia Was Bought by Jawbone – For ~$100M • Zeo Sleep Monitor – Closed Down in 2013 More Mergers Likely as the Shakeout Continues
  11. 11. RevUp! Completes the Behavior Feedback Loop Source: Samir Damani, MD Revolution
  12. 12. From Measuring Macro-Variables to Measuring My Internal Variables – What Did I Learn? www.technologyreview.com/biomedicine/39636
  13. 13. From One to a Billion Data Points Defining Me: The Exponential Rise in Body Data in Just One Decade! Billion:Microbial Genome My Full DNA, MRI/CT Images Improving Body SNPs Million: My DNA SNPs, Zeo, FitBit Blood Variables One: My Weight Weight Discovering Disease Hundred: My Blood Variables
  14. 14. Visualizing Time Series of 150 LS Blood and Stool Variables, Each Over 5-10 Years Calit2 64 megapixel VROOM
  15. 15. I Discovered I Had Chronic Inflammation by Tracking Complex Reactive Protein In My Blood Samples 27x Upper Limit Antibiotics Normal Range <1 mg/L Antibiotics Normal CRP is a Generic Measure of Inflammation in the Blood
  16. 16. But by Using Stool Analysis Time Series, I Discovered I Had Episodically Excursions of My Immune System Typical Lactoferrin Value for Active IBD 124x Upper Limit So I Reasoned My Gut Microbiome Ecology Must Be Disrupted and Dynamically Changing Normal Range <7.3 µg/mL Antibiotics Antibiotics Lactoferrin is a Protein Shed from Neutrophils An Immune System Antibacterial that Sequesters Iron
  17. 17. Indeed, My Cultured Gut Bacterial Abundance Time Series Revealed an Oscillatory Microbiome Ecology LS Data from Yourfuturehealth.com
  18. 18. Startups are Already in the Internal Quantified Self Space! WellnessFX Just Acquired By Health Elements
  19. 19. Confirming the IBD Hypothesis: Finding the “Smoking Gun” with MRI Imaging Liver Transverse Colon Small Intestine I Obtained the MRI Slices From UCSD Medical Services and Converted to Interactive 3D Working With Calit2 Staff & DeskVOX Software Descending Colon MRI Jan 2012 Cross Section Diseased Sigmoid Colon Major Kink Sigmoid Colon Threading Iliac Arteries
  20. 20. Why Did I Have an Autoimmune Disease like IBD? Despite decades of research, the etiology of Crohn's disease remains unknown. Its pathogenesis may involve a complex interplay between host genetics, immune dysfunction, and microbial or environmental factors. --The Role of Microbes in Crohn's Disease So I Set Out to Quantify All Three! Paul B. Eckburg & David A. Relman Clin Infect Dis. 44:256-262 (2007) 
  21. 21. The Cost of Sequencing a Human Genome Has Fallen Over 10,000x in the Last Ten Years! This Has Enabled Sequencing of Both Human and Microbial Genomes
  22. 22. Single Nucleotide Polymorphisms (SNPs) Make Up About 90% of All Human Genetic Variation Person A SNPs Occur Every 100 to 300 Bases Along Human DNA Person B www.23andme.com Tracks One Million SNPs
  23. 23. I Wondered if Crohn’s is an Autoimmune Disease, Did I Have a Personal Genomic Polymorphism? From www.23andme.com ATG16L1 Polymorphism in Interleukin-23 Receptor Gene — 80% Higher Risk of Pro-inflammatory Immune Response IRGM NOD2 SNPs Associated with CD Now Comparing 163 Known IBD SNPs with 23andme SNP Chip and My Full Human Genome
  24. 24. Fine Time-Resolution Revealed Immune Dysfunction in the Innate and Adaptive Immune System LS Data from Yourfuturehealth.com Lysozyme & SIgA From Stool Tests Innate Immune System Normal Therapy: 1 Month Antibiotics +2 Month Prednisone Adaptive Immune System Normal
  25. 25. I Had Carried Out Observations in Optical, Radio, and X-Ray on the Andromeda Galaxy in the 1980s A Galaxy Contains One Hundred Billion Stars But the Human Gut Contains 1000 Times As Many Microbes!
  26. 26. Now I am Observing the 100 Trillion Non-Human Cells in My Body Your Body Has 10 Times As Many Microbe Cells As Human Cells 99% of Your DNA Genes Are in Microbe Cells Not Human Cells Inclusion of the Microbiome Will Radically Change Medicine
  27. 27. 2012 Was the Year of Human Microbiome
  28. 28. I Spent Decades Studying the Ecological Dynamics of Coral Reefs Pristine Degraded My 120 Gallon Home Salt Water Coral Reef Aquarium in Illinois My Snorkeling Photos From Coral Reefs
  29. 29. When We Think About Ecological Diversity We Typically Think of the Wide Range of Animals But All These Animals Are in One SubPhylum Vertebrata of the Chordata Phylum All images from Wikimedia Commons. Photos are public domain or by Trisha Shears & Richard Bartz
  30. 30. Think of These Phyla of Animals When You Consider the Biodiversity of Microbes Inside You Phylum Chordata Phylum Cnidaria Phylum Echinodermata Phylum Annelida Phylum Mollusca Phylum Arthropoda All images from WikiMedia Commons. Photos are public domain or by Dan Hershman, Michael Linnenbach, Manuae, B_cool
  31. 31. However, The Evolutionary Distance Between Your Gut Microbes Is Much Greater Than Between All Animals Last Slide Green Circles Are Human Gut Microbes Evolutionary Distance Derived from Comparative Sequencing of 16S or 18S Ribosomal RNA Source: Carl Woese, et al
  32. 32. Quantifying Our Human Superorganism: Distribution of Microorganism Ecology on Our Bodies Nature Reviews Microbiology v.9, p. 279 (2011)
  33. 33. Intense Scientific Research is Underway on Understanding the Human Microbiome June 8, 2012 June 14, 2012 From Culturing Bacteria to Sequencing Them
  34. 34. The Adult Healthy Gut Microbiome Is Remarkably Stable Over Time Source: Eric Alm, MIT
  35. 35. To Map Out the Dynamics of My Microbiome Ecology I Partnered with the J. Craig Venter Institute • JCVI Did Metagenomic Sequencing on Six of My Stool Samples Over 1.5 Years • Sequencing on Illumina HiSeq 2000 – Generates Reads (100 Bases) – Run Takes ~14 Days – My 6 Samples Produced Illumina HiSeq 2000 at JCVI – 190.2 Gbases of Data • JCVI Lab Manager, Genomic Medicine – Manolito Torralba • IRB PI Karen Nelson – President JCVI Manolito Torralba, JCVI Karen Nelson, JCVI
  36. 36. We Downloaded Additional Human Gut Microbiome Data from the NIH For Comparative Analysis 35 “Healthy” Individuals: 1 Point in Time 2 Ulcerative Colitis Patients: 1 Point in Time and 5 Points in Time 5 Ileal Crohn’s Patients: 3 Points in Time Total of 5 Billion Illumina Reads Source: Jerry Sheehan, Calit2; Weizhong Li, Sitao Wu, CRBS, UCSD
  37. 37. We Used SDSC’s Gordon Data-Intensive Supercomputer to Analyze a Wide Range of Gut Microbiomes Source: Weizhong Li, Sitao Wu, CRBS, UCSD Our Team Used 25 CPU-Decades To Compute the Comparative Gut Microbiome of My Time Samples and Our Healthy and IBD Controls Starting With the 5 Billion Illumina Reads Received from JCVI Enabled by a Grant of Time on Gordon from SDSC Director Mike Norman
  38. 38. Using Scalable Visualization Allows Comparison of the Relative Abundance of 200 Microbe Species Comparing 3 LS Time Snapshots (Left) with Healthy, Crohn’s, UC (Right Top to Bottom) Calit2 VROOM-FuturePatient Expedition
  39. 39. Lessons from Ecological Dynamics I: Gut Microbiome Has Multiple Relatively Stable Equilibria “The Application of Ecological Theory Toward an Understanding of the Human Microbiome,” Elizabeth Costello, Keaton Stagaman, Les Dethlefsen, Brendan Bohannan, David Relman Science 336, 1255-62 (2012)
  40. 40. Disease State Has a Different Microbiome Equilibrium Than Healthy Expansion of Actinobacteria Collapse of Bacteroidetes Explosion of Proteobacteria
  41. 41. Time Series Reveals Ecological Dynamics of My Gut Microbiome by Phyla Therapy Six Metagenomic Time Samples Over 16 Months
  42. 42. Lessons From Ecological Dynamics II: Invasive Species Dominate After Major Species Destroyed  ”In many areas following these burns  invasive species are able to establish themselves,  crowding out native species.” Source: Ponderosa Pine Fire Ecology http://cpluhna.nau.edu/Biota/ponderosafire.htm
  43. 43. Almost All Abundant Species (≥1%) in Healthy Subjects Are Severely Depleted in Larry’s Gut Microbiome
  44. 44. Top 20 Most Abundant Microbial Species In LS vs. Average Healthy Subject 152x 765x 148x Number Above LS Blue Bar is Multiple of LS Abundance Compared to Average Healthy Abundance Per Species 849x 483x 220x 201x169x 522x Source: Sequencing JCVI; Analysis Weizhong Li, UCSD LS December 28, 2011 Stool Sample
  45. 45. Next Step: Time Series of Metagenomic Gut Microbiomes and Immune Variables in an N=100 Clinic Trial Goal: Understand The Coupled Human Immune-Microbiome Dynamics In the Presence of Human Genetic Predispositions Drs. William J. Sandborn, John Chang, & Brigid Boland UCSD School of Medicine, Division of Gastroenterology
  46. 46. From War to Gardening: New Therapeutical Tools for Managing the Microbiome “I would like to lose the language of warfare,”  said Julie Segre, a senior investigator at  the National Human Genome Research Institute.  ”It does a disservice to all the bacteria  that have co-evolved with us  and are maintaining the health of our bodies.”
  47. 47. Where I Believe We are Headed: Predictive, Personalized, Preventive, & Participatory Medicine I am Lee Hood’s Lab Rat! www.newsweek.com/2009/06/26/a-doctor-s-vision-of-the-future-of-medicine.html
  48. 48. Thanks to Our Great Team! UCSD Metagenomics Team JCVI Team Weizhong Li Sitao Wu Karen Nelson Shibu Yooseph Manolito Torralba SDSC Team Calit2@UCSD Future Patient Team Jerry Sheehan Tom DeFanti Kevin Patrick Jurgen Schulze Andrew Prudhomme Philip Weber Fred Raab Joe Keefe Ernesto Ramirez Michael Norman Mahidhar Tatineni Robert Sinkovits UCSD Health Sciences Team William J. Sandborn Elisabeth Evans John Chang Brigid Boland David Brenner

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